Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK.
Glucocorticoids are highly effective in the control of many inflammatory and immune diseases. Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, the molecular basis for the inhibitory effect of glucocorticoids on mucin overproduction, a hallmark of chronic respiratory diseases, still remains unclear. Here we show that glucocorticoids markedly inhibit up-regulation of MUC5AC induced by NTHi, a major human bacterial pathogen causing chronic obstructive pulmonary disease and otitis media. Inhibition of NTHi-induced MUC5AC expression by dexamethasone occurs at the level of p38 MAPK via glucocorticoid receptor. Moreover, glucocorticoids up-regulate MKP-1 expression, which in turn leads to p38 dephosphorylation and the subsequent inhibition of NTHi-induced MUC5AC expression. These studies provide new insight into the molecular mechanism underlying glucocorticoid therapy and may lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with NTHi infections.
Komatsu
Kensei
K
Department of Microbiology & Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Jono
Hirofumi
H
Lim
Jae Hyang
JH
Imasato
Akira
A
Xu
Haidong
H
Kai
Hirofumi
H
Yan
Chen
C
Li
Jian-Dong
JD
D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000627:therapeutic use*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005938:Glucocorticoids / Q000627:therapeutic use*; D006192:Haemophilus Infections / Q000188:drug therapy* / Q000382:microbiology; D006193:Haemophilus influenzae; D006801:Humans; D055271:Mucin 5AC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010033:Otitis Media / Q000188:drug therapy* / Q000382:microbiology; D010766:Phosphorylation / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000382:microbiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005938:Glucocorticoids; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1